Robert Pavletic

Dr.Gottardo

Chem-4211-WA

March 23, 2017

Free Radical Reactions

Free radical chemistry is a broad and diverse topic that has been covered extensively in
the fields of biochemistry, organic synthesis and polymer chemistry. To properly understand
the applications of free radical reactions it is important to evaluate free radical chemistry from
several different perspectives. The first paper reviewed Free radical oxidation of cholesterol
and its precursors: Implications in cholesterol biosynthesis disorders provides a good insight into
how free radical oxidation affects human biology and the problems that can arise from random
free radical oxidation. The second paper reviewed Synthesis of biaryls via intramolecular free
radical ipso-substitution reactions provided a good example of the use of free radical chemistry
as an alternative to a previous synthetic method. The third paper Radical copolymerization of
N-phenylmaleimide and diene monomers in competition with diels–alder reaction provided a
look into the vast field of radical polymerization as well as outlined some of the challenges
associated with the copolymerization of monomer chains. Together these three articles give a
diverse and extensive look into free radical chemistry.

A free radical is a molecule that contains one or more unpaired electrons1. Free radicals
are electron deficient2. Despite being electron deficient, most free radicals are uncharged
meaning their chemistry is different than that of other electron-deficient species such as
carbocations and carbenes2. One example the alkyl radical ·CR3 is a seven electron, electron
deficient species with its geometry considered to be a shallow pyramid2. The energy required
to invert this pyramid is small and thus the alkyl radical is very reactive2. It is usually
acceptable to think of alkyl radicals as sp2-hybridised2. Free radicals are produced most
commonly by the hemolytic cleavage of covalent bonds as observed in figure12.

Figure 1: Hemolytic cleavage of Br2 by light

Although hemolytic cleavage by light is the most common type of free radical formation,
free radical initiators may be formed by the application of heat(thermal), ultraviolet and visible
light, ionizing light, redox reagents, and electricity(electrochemistry)2. The formation of radicals
is dependent on the bond energy between the molecules undergoing cleavage 2. This is known
as the bond energy2. Radicals that require more energy top form tend to be less stable2. The
formation of radicals through homolytic bond cleavage most commonly occurs between two
atoms of comparable electronegativity2. This is often diatomic molecules such as Br2, Cl2, or
molecules such as oxygen (3.44) and nitrogen (3.04) that similar electronegativity’s2.

Free Radical reactions can be broken down into three main steps; initiation, propagation
and termination. The initiation step is the step in which a free radical is formed 3. In this sense
initiation can be defined as the net increase in the amount of free radicals present in the
reaction2. The next step in a free radical reaction is propagation. Propagation is the step in
which the free radical reacts with a molecule to cause a change to such molecule 2. This occurs
as free radical substitution, free radical addition or free radical ocidation2. In free radical
substitution the free radical molecule is substituted onto the target molecule in place of a
group on the target molecule that the leaves2. This target molecule then itself becomes a
radical1. In free radical addition the radical is added to the target molecule making the
molecule itself a radical1. This new radical may then undergo further addition causing a chain
reaction1. This is very common in polymer chemistry1. One such example, polyethylene, will
have a worldwide demand of 99.6 million metric tons in 20184. Free radical oxidation occurs
when free radicals cause the oxidation of a target molecule5. Free radical oxidation in biological
tissues has been linked with many diseases5. During propagation the amount of free radicals
remains the same2. Termination is the final step in free radical reactions. In this step the free
radicals are eliminated. This is most commonly done by reacting two radicals together to
create molecules with balanced numbers of electrons2. Free radical reactions can then be
simplified as initiation; the step with a net increase in the amount of free radicals, propagation;
no net change in the amount of free radicals and termination; net decrease in the amount of
free radicals. A good example of this was given in the first paper studied (Free radical oxidation
of cholesterol and its precursors: Implications in cholesterol biosynthesis disorders)5.
Figure 2: The simplified free radical reactions studied in the paper Free radical oxidation of
cholesterol and its precursors: Implications in cholesterol biosynthesis disorders

The first paper dealing with free radical reactions that was reviewed was Free radical
oxidation of cholesterol and its precursors: Implications in cholesterol biosynthesis disorders by
L. Xu ∗ and N. A. Porter. This paper focused on the free radical oxidation of cholesterol and its
precursors and their association with a number of human diseases. The reason for this study is
that cholesterol is found in mammalian cells and tissues and plays a key role in maintaining
plasma membrane integrity, activation of the hedgehog pathway during embryonic
development, lipid-raft-mediated cell signaling, and myelin formation and the free radical
oxidation of cholesterol and its precursors has been linked to several human diseases such as
Alzheimer's disease, retinal degradation, age-related macular degradation, cataract and
Nieman-Pick C1 disease5. The free radical oxidation of cholesterol and its precursors were
studied to observe their reactivity’s and to observe and understand diseases associate with the
free radical oxidation of these precursors5. From this possible treatment of these diseases
could be developed5. The sythesis of cholesterol and the precursors studied is observed in the
following figure (figure 3)5.
Figure 3Cholesterol and its precursors from Free radical oxidation of cholesterol and its
precursors: Implications in cholesterol biosynthesis disorders by L. Xu ∗ and N. A. Porter.

The propagation reaction of the peroxy radical is the rate determining step in the free
radical oxidation of lipids (Figure 2)5. This is done by two different processes5. The first is
hydrogen atom transfer5. In this process a hydrogen atom is transferred from a donor to the
chain-carrying peroxy radical (figure 2, (a)) 5.The second process is peroxy radical addition to a
double bond (figure 2(b)) 5. Using the hydrogen transfer method the hydrogen transfer rate
constants were determined and tabulated5 (Table 1)5.

1) kH per H-atom is shown in the parentheses.

2) Number of substituents on the delocalized radical intermediates.
3) Dihedral angles between the reactive C – H and the double bond plane and the values in the parenthesis show the diff erence from 90 ° . 4)
Dihedral angles between the planes containing individual double bond.
5) endo : radical delocalize within the same ring; exo : radical delocalize across rings.
6) The angle between the planes C 5,6,7 and C 7,8,9
7) The angle between C 5,6,7 and C 7,8,14 . h value was obtained by extrapolating the rate constants of oleate and linoleate using their
computed bond dissociation enthalpy
Table 1 Summary of the results of the free radical oxidation of cholesterol and its precursors 5
 From the results of testing cholesterol and it`s precursors against similarly sized fatty
acids and cyclohexane and it`s substituted relatives several conclusions were made 5. The first
conclusion was that the reactivity of sterols was higher than their fatty acid analogs and their
flexible cyclic analogs5. This was partly due to the fact that the sterols were better hydrogen
donors5. Another contributing factor was that sterols in general have more alkyl substituents
on double bonds than those in fatty acids which lead to sterols having a lower activation
energy5. A third factor affecting the reactivity of the sterols was the dihedral angles between
the reactive C-H bond and the adjacent double bond and the planetary double bond 5. In
general the sterols required less molecular reorientation to reach the transition state allowing
for lower activation energy5. It was also found that dienes that adopt cisoid conformations
tend to be more reactive than those adopting trannll soid conformations.

When free radical oxidation occurred via peroxy radical addition to a double bond it was
found that the peroxy radical addition was generally followed by an intramolecular homolytic
substitution, which gave an epoxide as the final product5. It was found that double bonds that
were more substituted at the center distant from the site of addition would be more reactive
than a less substituted structure5. The resulting stability was then found to be
Tertiary>secondary>primary5. A second conclusion that was made was that a conjugated
diene would be more reactive than a non-conjugated diene since a more stable allylic radical
would be formed, this partially explains the high reactivity of 7-DHC5. It was also found that if
similar radicals are formed, a peroxyl radical would primarily add to the carbon center that was
less hindered5. Since the resulting radicals of sterols are generally more stable than their fatty
acid counterparts it was observed that sterols are normally more reactive5.

The most reactive cholesterol precursor found was 7-dehydrocholesterol(7-DHC)5. The

normal function of 7-DHC in the body is as a precursor to vitamin D3. 7-DHC has been
suggested to be a contributing factor in Smith–Lemli–Opitz syndrome(SLOS)5. SLOS exhibits a
broad range of phenotypes including multiple congenital malformations, neurological defects,
mental retardation, autism-like behavior, and photosensitivity5. The high biological activity of
7-DHC was first reported in 1996 be De Fabiani5. In 2006, Fliesler suggested that the retinal
degradation in a rat model caused by SLOS was caused by elevated levels of lipid peroxides
derived from 7-DHC. Gaoua had also found that products generated from the photooxidation
of 7-DHC induced growth retardation in rat embryos5. In addition to 7-DHC there is also
evidence to suggest that ,14-dienol, lathosterol, and zymostenol, may also serve as strong free
radical peroxidation substrates. This would suggest that oxidative stress may be associated
with other cholesterol biosynthesis disorders5.

The second article that dealt with free radical reactions was Synthesis of biaryls via
intramolecular free radical ipso-substitution reactions by Feroze Ujjainwalla, Maria Lucília E.N.
da Mata, Andrew M.K. Pennell , Carmen Escolano, William B. Motherwell and Santiago
Vazquez. This article dealt with the synthesis of biaryls using an intramolecular free radical
[1,5]-ipso-substitution6. The biaryl moiety is commonly found in natural products with a wide
variety of structures6. Polyketides, terpenes, lignans, coumarins, flavonoids, tannins and
alkaloids all contain a biaryl moiety6. This class of compounds may be used as biologically active
natural products, as chiral reagents, as crown ethers, as polymers, as organic materials for non-
linear optics and also as the foundation of chiral liquid crystals6. As a result of their diverse
number of uses, several methods have been developed for biaryl construction 6. The most
common method for preparing biaryls being transition metal mediated coupling reactions6.
Problems arise with this method when severely hindered products are required and when the
reaction involves two rings of incompatible electronic characteristics6. For this reason, the use
of free radicals in the synthesis of biaryls has become much more common over the last 40
years6. The authors of the article modified a simple free radical chain reaction of a primary
iodide by Bu3SnH when it was observed that significant quantities of the product had
undergone a 1, 5-ipso substitution(2 in figure 5)6. This can be observed in the following figure
(figure 4)6.

Figure 4: Reactants and products from the free radical chain reaction of a primary iodide by
Bu3SnH from Synthesis of biaryls via intramolecular free radical ipso-substitution reactions

From this it was concluded that the modification of this reaction could lead to a general biaryl
synthesis using a free radical ipso-substitution.

To test this theory a rearrangement precursor (5a) was created and then methylated
(6a) to sulfonamide to improve the likelihood of a radical reaction outcome6. This was done at
a variety of different reaction conditions involving the concentrations of the stannane reagent,
the length of the react, the equivalents of stannane, the equivalents of
Azobisisobutyronitrile(AIBN), the use of refluxing anisole and the use of TIMSH as a redactor 6.
This can be observed in the following figures (figure 5)6 and figure 66.
 .

Figure 5: Reactants and Products of the 1,5-ipso-substitution(7a) and products of the 1,6-
addition(8a) from Synthesis of biaryls via intramolecular free radical ipso-substitution reactions

Figure 6: the proposed mechanisms of the 1,5-Ipso-substitution and the 1,6 addition from
Synthesis of biaryls via intramolecular free radical ipso-substitution reactions

From these tests it was found that the conversion of the sulfonamide was dependent on
the amount of the radical initiator (AIBN) used, meaning the chain processes involved are very
efficient6. The equivalents of Bu3SnH seemed to be irrelevant6. The increased concentration
of the stannane solution increased the ratio of the 1,5-Ipso-substitution products to the
products of the 1,6 addition6. This would suggest that that at least one step outlined in figure 7
is reversible6. It was also observed that higher temperatures caused an increase in the ratio of
the 1,5-Ipso-substitution product6. The final observation was that the use of Chatgilialoglu’s
reagent caused an increase of the amount of 1, 6-addition product observed6. Using this
information a total of 100 reactants and products were examined to better determine the
viability of the 1,5-Ipso-substitution method to produce biaryls as well as the possibility of a 1,6-
Ipso-substitution product 6.

The continued evaluation of 1,5-Ipso-substitution product against 1,6-addition was

heavily discussed in the article. The success of 1,5-Ipso-substitution product with the
sulfonamide led to the authors attempting similar reactions with closely related reactants(17a
and 19in the paper)6. This was however unsuccessful in producing any 1,5-Ipso-substitution
product6. The effects of substituents on the acceptor ring were then studied. It was found that
the location of a methyl on the ortho acceptor ring greatly favoured 1,5-Ipso-substitution6. It
was found that para-fluoro substituents hindered 1,5-Ipso-substitution and retarted 1,6
addition as well6. It was also observed that para methoxy groups were more efficient in driving
1,5-Ipso-substitution than para-methyl groups due to their ability to stabilize the spirocyclic
intermediate. When a meta-carbo-methoxy group was used it was found to be a poor director
for 1,5-Ipso-substitution6. It was also confirmed that the location of an appropriately placed
heteroatom could allow for the synthesis of hetero-biaryls6.

Due to the success of 1,5-Ipso-substitution against 1,6 addition it was theorised

that 1,-Ipso-substitution could have a similarly high selectivity against 1,7-addition6. Five
different sulfonyl substituted aromatic derivatives were tested 6. Using similar reasoning and
reaction mechanisms to 1,5-Ipso-substitution against 1,6 addition the authors were
unsuccessful in proving the ability of 1,6-Ipso-substitution to be favoured over 1,7-addition8.
The authors initially believed that a 6-membered ring would be more favorable than a 7-
membered ring and that using the same thinking that gave them favourable results for 1,5-Ipso-
substitution against 1,6 addition would allow them to find evidence of a successful 1,6-Ipso-
substitution over 1, 7 addition6. It was proved incorrect as the conformational factors in the
tethering chain of the reaction ultimately controlled the final products of the reaction.

Overall, the authors were able to prove that intramolecular free radical 1,5-Ipso-
substitution provided a flexible reaction mechanism to hindered biaryl and heterobiaryls 6. This
was done using readily prepared sulfonate and sulfonamide tethering chains6. This process was
improved by appropriately placed electron drawing/donating groups located on the ortho
position of the acceptor ring which drove the product toward 1,5-Ipso-substitution.

The third paper dealing that dealt with free radical reactions was Radical
copolymerization of N-phenylmaleimide and diene monomers in competition with diels–alder
reaction by Akikazu Matsumoto and Daisuke Yamamoto. This article dealt with free radical
reactions in regards to polymerization7. Radical reactions are very common in polymer
chemistry and are of extreme industrial importance1. Some examples of products of radical
polymerization reactions include polyacrylonitrile (used for carpeting and clothing), low density
polythethylene(used for films, sheeting found in plastic bags electrical wiring), and
polyvinylchloride( calendered products such as floor coverings, shower curtains, rainwear and
handbags)1. Radical polymerization undergoes initiation, followed by the propagation step to
give long chain reactions which result in long polymer chains very rapidly1. When the chain is of
sufficient length the growth is stopped via termination1. One such type of radical
polymerization is alternating radical copolymerization7. An example of this can be observed in
the following figure (Figure 7)7.

Figure 7: Radical alternating copolymerization of MCP and RMI from Radical copolymerization
of N-phenylmaleimide and diene monomers in competition with diels–alder reaction

This article deals specifically with alternating radical copolymerization7. Alternating

radical copolymerization allows for the synthesis of high molecular weight copolymers in a good
yield, well defined alternating sequence structures independent of the ratio of copolymer
found in the feed and the ability to use various monomers7. When substituted maleimides
(RMI) are used as the electron-accepting monomers they readily provide alternating
copolymers with excellent thermal, optical, and mechanical properties during radical
copolymerization7. Examples of these electron-accepting monomers are styrene, vinyl ethers,
and isobutene7. These substituted maleimides, however, react with 1,3 diene compounds to
produce diels alder products rather than alternating copolymers7. This article examines these
two competing reactions in an attempt to find conditions that favour the production of the
alternating copolymer product as opposed to the diels alder product7. In the study, the
copolymers of N-phenylmaleimide with various diene monomers found in figure 8 7. The
reaction behaviour of the diene monomers as well as the structures and and properties
obtained through radical polymerization with N-phenylmaleimide with was investigated7.

Figure 8: Diene monomers used in this study and their chemical structures from Radical
copolymerization of N-phenylmaleimide and diene monomers in competition with diels–alder
reaction
 When these diene monomers were reacted with N-phenylmaleimide the resulting data
was obtained and placed in a table (table 2). This copolymerization was done by the following
procedure7. N-phenylmaleimide was placed in a glass ampoule with a diene monomer, a
radical initiator, and a solvent7. After the freeze–thaw cycles were completed the ampoule
was sealed7. The next step involved the solution being heated at a specific temperature for a
specific amount of time7. After heating the polymerization mixture was decanted into a large
amount of methanol to precipitate the copolymers, at which point they filtered out, washed,
then dried in vacuo. Copolymer yield was determined gravimetrically, while composition of the
repeating units in the copolymers was determined by 1H NMR spectroscopy.

Table 2: Results of the copolymerization of N-phenylmaleimide with selected diene monomers

and the thermal properties of the subsequent copolymers from Radical copolymerization of N-
phenylmaleimide and diene monomers in competition with diels–alder reaction
 The copolymers with the greatest yields were MCP and T17. This was explained by their
cyclic monomer structure with a fixed s-trans configuration7. DMPD, HD and PhMI all displayed
high copolymerization yields as well7. Overall the selectivity of a diene monomer to undergo
radical copolymerization or a Diels-alder reaction was dependent on the monomer7. The
degree to which that diene monomer could undergo a radical copolymerization was dependent
on the monomers ability to supress a Diels-alder reaction7. Diene monomers with an
exomethylene moiety and a fixed-s-trans diene structured showed the greatest ability to
supress the Diels-alder reaction and thus showed the highest reactivity toward
copolymerization7. Furthermore, non-cyclic dienes with hindered substituents also showed
good reactivity toward radical copolymerisation7. Tuning of the reaction conditions, namely
temperature and solvents had little effect7. One such exception was radical polymerization at
low temperature in the presence of an azo initiator with a large decomposition rate constant7.
From these reactions, the copolymers of the RMIs with diene monomers obtained could be
useful for application fields related to optics and optoelectronics materials.

The three articles studied each gave a different perspective on the topic of free radical
chemistry. The first article Free radical oxidation of cholesterol and its precursors: Implications
in cholesterol biosynthesis disorders gave an understanding on the high reactivity of free
radicals in biological systems5. The ability of free radicals to oxidise cholesterol and its
precursors as discussed in the article helped accentuate the high reactivity of free radicals in
biological systems as well as described some of the serious health problems associated with
free radical oxidation in the body7. The second article Synthesis of biaryls via intramolecular
free radical ipso-substitution reactions showed the usefulness of free radicals in organic
synthesis. The article also helped emphasize the use of free radical reactions as an alternative
synthesis when steric hindrance is a problem6. The third article Radical copolymerization of N-
phenylmaleimide and diene monomers in competition with diels–alder provided a good insight
into the extensive field of radical polymerization7. The article also outlined some of the
challenges associated with the copolymerization of monomer chains especially when
copolymerization is competing with another side reaction7. In conclusion the three articles
discussed gave an extensive overview of free radical reactions and provided different
perspectives on free radical chemistry.
References

1. Carraher, Charles E., Jr. Introduction to polymer chemistry. Vol. 3. N.p.: CRC Press,
n.d. Print. Chapter 7 Free Radical Chain Polymerization(Addition Polymerization)
2. Neuman, Robert C., Jr. Organic Chemistry . N.p.: n.p., n.d. Web.chem.ucsb.edu. Web.
Chapter 11 Free Radical Substitution and Addition Reactions
3. Atkins, Peter , and Julio De Paulo. Physical chemistry Thermodynamics, structure and
change. 10th ed. N.p.: n.p., n.d. Print.
4. "Global Demand For Polyethylene To Reach 99.6 Million Tons In 2018." Gas and
Pipeline Journal. N.p., n.d. Web. 22 Mar. 2017.
5. Xu, L., and N. A. Porter. "Free radical oxidation of cholesterol and its precursors:
Implications in cholesterol biosynthesis disorders." Free Radical Research 49.7
(2014): 835-49
6. Feroze Ujjainwalla, Maria Lucília E.N da Mata, Andrew M.K. Pennell, Carmen
Escolano, William B. Motherwell, and Santiago Vazquez. "Synthesis of biaryls via
intramolecular free radical ipso-substitution reactions ." Tetrahedron 71 (2015): n.
pages 6701-6719.
7. Akikazu Matsumoto , and Daisuke Yamamoto. "Radical copolymerization of N-
phenylmaleimide and diene monomers in competition with diels–alder ." Journey of
Polymer Science Part A:Polymer Chemistry 54.22 (2016): 3616-3625